A fundamental tenet of cancer chemotherapy is that the "curability" of neoplasm is dependent upon the number of viable cells present at the start of therapy. Therefore any intervention which would reduce the total tumor burden before initiation of chemotherapy would be efficacious. The role of blood platelets in the hematogenous spread of malignant disease is presently unclear. The use of anticoagulant therapy has been less than satisfactory probably due to lack of specificity of the agents. We propose that alteration of the platelet thromboxane A2 - vascular endothelial prostacyclin balance in favor of proaggregatory compounds such as thromboxane A2 favors survival of circulating tumor cells and establishment of successful metastatic lesions. Preliminary results with B16 melanoma cells indicate that the thromboxane synthetase inhibitor 1-carboxyheptylimidazole is a potent antimetastatic agent. This effect is potentiated by the phosphodiesterase inhibitor, theophylline. We propose to investigate the effects of platelet thromboxane synthetase inhibitors and receptor antagonists on metastasis of the B16 melanoma, Cloudman melanoma and Lewis Lung carcinoma. Drug intervention in prevention of metastasis from tail vein injected tumor cells and subcutaneous tumors will be assessed. The temporal relationship between tumor cell entrapment and platelet aggregation will also be studied using 125I Udr labelled tumor cells and 51Cr labelled platelets. Possible synergism between TXA2 inhibitors and phosphodiesterase inhibitors will be examined. In addition, I present evidence that TXA2 inhibitors decrease primary tumor growth and tumor cell DNA synthesis. The role of TXA2 and inhibitors of TX synthetase on tumor cell growth in vitro and in vivo will be assessed. The proposed research is expected to yield important data concerning the efficacy of specifically directed anticoagulant therapy which could possibly also be used as a primary cancer chemotherapeutic agent.